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CA2669399A1 - Thienopyrimidinones for treatment of inflammatory disorders and cancers - Google Patents

Thienopyrimidinones for treatment of inflammatory disorders and cancers Download PDF

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Publication number
CA2669399A1
CA2669399A1 CA002669399A CA2669399A CA2669399A1 CA 2669399 A1 CA2669399 A1 CA 2669399A1 CA 002669399 A CA002669399 A CA 002669399A CA 2669399 A CA2669399 A CA 2669399A CA 2669399 A1 CA2669399 A1 CA 2669399A1
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Prior art keywords
compound
optionally substituted
alkyl
heteroalkyl
ring
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Abandoned
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CA002669399A
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French (fr)
Inventor
Stephen L. White
Edward A. Kesicki
Eugene Thorsett
Fuqiang Ruan
Francine Farouz
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Eli Lilly and Co
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Endocrinology (AREA)
  • Neurology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Otolaryngology (AREA)
  • Biomedical Technology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The current invention provides compounds of formula (1): wherein: one of Q1, Q2 and Q3 is S, and the other of two of Q1, Q2 and Q3 are -CR1-, which are inhibitors of PI3K-delta. These compounds are useful for treatment of conditions mediated by PI3K-delta, such as hematopoietic cancers, immune disorders, and bone resorption disorders. The invention further provides pharmaceutical compositions comprising a compound of formula (1) and methods of using these compounds and compositions to treat conditions mediated by PI3K-delta.

Claims (24)

1. A compound of the formula (1):

wherein:
one of Q1, Q2 and Q3 is S, and the other of two of Q1, Q2 and Q3 are -CR1-;
wherein each R1 is independently H, halo, OR, NR2, NROR, NRNR2, SR, SOR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRCOOR, NRCOR, CF3, CN, COOR, CONR2, OOCR, COR, or NO2, or R1 can be an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl groups, wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl, and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two N, O or S as ring members;
and wherein each R group other than H, and each ring formed by linking two R groups together, is optionally substituted;

Z is a bond, or is O, NR2, C1-C6 alkylene or C1-C6 heteroalkylene, each of which is optionally substituted with up to two C1-C6 alkyl or C2-C6 heteroalkyl groups, where two of said alkyl or heteroalkyl groups can optionally cyclize to form a 3-7 membered ring containing up to two heteroatoms selected from O, N and S as ring members;

R3 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with up to three R1, or R3 can be H if Z is not a bond;

L is selected from the group consisting of -C(R2)2-, -C(R2)2-C(R2)2-, -C(R2)2-NR2-, and -C(R2 )2-S(O)n-, wherein each R2 is independently H or an optionally substituted member selected from C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, and n is 0-2;
and two R2, if present on L, can cyclize to form a 3-7 membered ring that may contain up to two heteroatoms selected from N, O and S as ring members;
Het is a monocyclic or bicyclic ring system wherein at least two ring atoms are N
and wherein at least one ring is aromatic, and Het is optionally substituted with up to three substituents selected from R4, N(R4)2, S(O)p R4, OR4, halo, CF3, CN, NR4OR4, NR4N(R4)2, SR4, SOR4, SO2R4, SO2N(R4)2, NR4SO2R4, NR4CON(R4)2, NR4COOR4, NR4COR4, CN, COOR4, CON(R4)2, OOCR4, COR4, or NO2, wherein each R4 is independently H or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl, and wherein two R4 on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two heteroatoms selected from N, O and S;
wherein the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, CF3, CN, =0, =N-CN, =N-OR', =NR', OR', NR'2, SR', SO2R', SO2NR'2, NR'SO2R', NR'CONR'2, NR'COOR', NR'COR', CN, COOR', CONR'2, OOCR', COR', and NO2, wherein each R' is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and =O;
and wherein two R' on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S; and p is 0-2;

or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein Q1 is S.
3. The compound of claim 1, wherein Q2 is S.
4. The compound of claim 1, wherein Q3 is S.
5. The compound of any of claims 1-4, wherein Z is a bond and R3 is optionally substituted aryl.
6. The compound of claim 5, wherein Het is an optionally substituted bicyclic group consisting of two aromatic rings fused together, wherein each of the two aromatic rings contains at least one N as a ring member.
7. The compound of claim 6, wherein Het represents a purine ring system.
8. The compound of claim 6, wherein Het represents a pyrazolopyrimidine ring system.
9. The compound of claim 6, wherein Het represents a pyrrolopyrimidine ring system.
10. The compound of any of claims 6-9, wherein L is CHR2.
11. The compound of any of claims 6-9, wherein L is -CHR2-NR2-.
12. The compound of any of claims 6-9, wherein L is -CHR2-S(O)n-, and n is 0 or 2.
13. The compound of any of claims 10-12, wherein L contains a chiral center that is in the S stereochemical configuration.
14. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof.
15. A method to treat a hematologic cancer, comprising administering to a subject diagnosed with a hematologic cancer an effective amount of a compound of any of embodiments 1-14.
16. The method of claim 15, wherein the hematologic cancer is leukemia.
17. The method of claim 16, wherein the leukemia is acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; chronic myelogenous leukemia; or hairy cell leukemia.
18. A method to treat an inflammatory disorder or immune disorder, comprising administering to a subject diagnosed with an inflammatory disorder or immune disorder an effective amount of a compound of any of claims 1-14.
19. The method of claim 18, wherein the inflammatory disorder or immune disorder is rheumatoid arthritis, multiple sclerosis, asthma, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, myasthenia gravis, Guillain-Barré syndrome, Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, vasculitis, hemolytic anemia, thrombocytopenia, psoriasis, type I (insulin dependent) diabetes, or allergic rhinitis.
20. A method to treat hypertension, comprising administering to a subject diagnosed with hypertension an effective amount of a compound of any of claims 1-14.
21. A pharmaceutical composition comprising a compound of any of claims 1-14, admixed with at least one pharmaceutically acceptable excipient.
22. The pharmaceutical composition of claim 21, which is a solid dosage form for oral administration.
23. Use of a compound of any of claims 1-14 for the manufacture of a medicament.
24. The use of claim 23, wherein the medicament is a medicament for the treatment of a hematological cancer or an immune disorder or hypertension.
or a pharmaceutically acceptable salt thereof.
CA002669399A 2006-11-13 2007-11-13 Thienopyrimidinones for treatment of inflammatory disorders and cancers Abandoned CA2669399A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US85885006P 2006-11-13 2006-11-13
US60/858,850 2006-11-13
PCT/US2007/084582 WO2008064018A1 (en) 2006-11-13 2007-11-13 Thienopyrimidinones for treatment of inflammatory disorders and cancers

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CA2669399A1 true CA2669399A1 (en) 2008-05-29

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US (1) US20100216820A1 (en)
EP (2) EP2441768A1 (en)
JP (1) JP5313909B2 (en)
KR (1) KR20090087027A (en)
CN (1) CN101605797A (en)
AU (1) AU2007323836B2 (en)
CA (1) CA2669399A1 (en)
IL (1) IL198596A0 (en)
NZ (1) NZ576997A (en)
SG (1) SG178786A1 (en)
WO (1) WO2008064018A1 (en)

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